Normal human pituitary gland and pituitary adenomas express cannabinoid receptor type 1 and synthesize endogenous cannabinoids: First evidence for a direct role of cannabinoids on hormone modulation at the human pituitary level

Little is known about the expression and function of cannabinoid receptor t ype 1 (CB1) in the human pituitary gland. The aim of this study was to inve stigate CB1 expression in human normal and tumoral pituitaries by in situ h ybridization and immunohistochemistry using an antibody against CB1. CB1 wa s found in corticotrophs, mammotrophs, somatotrophs, and folliculostellate cells in the anterior lobe of normal pituitary. After examination of 42 pit uitary adenomas, CB1 was detected in acromegaly-associated pituitary adenom as, Gushing's adenomas, and prolactinomas, whereas faint or no expression w as found in nonfunctioning pituitary adenomas. Experiments with cultured pi tuitary adenoma cells showed that the CB1 agonist WIN 55,212-2 inhibited GH secretion in most of acromegaly-associated pituitary adenomas tested and t hat the GB 1 antagonist SR 141716A was generally able to reverse this effec t. Moreover, WIN 55,212-2 was able to suppress GHRH-stimulated GH release, and this effect was not blocked by coincubation with SR 141716A, possibly i ndicating a non-CB1-mediated effect. In contrast, WIN 55,212-2 was ineffect ive on GH-releasing peptide-stimulated GH release. In four Gushing's adenom as tested, WIN 55,212-2 was not able to modify basal ACTH secretion. Howeve r, simultaneous application of CRF and WIN 55,212-2 resulted in a synergist ic effect on ACTH secretion, and this effect could be abolished by SR 14171 6A, demonstrating a CB1-mediated effect. In the single case of prolactinoma s tested, WIN 55,212-2 was able to inhibit basal secretion of PRL. Finally, the presence of endocannabinoids (anandamide and 2-arachidonoylglycerol) w as investigated in normal and tumoral pituitaries. All tumoral samples had higher contents of anandamide and 2-arachidonoylglycerol compared with the normal hypophysis. Moreover, endocannabinoid content in the different pitui tary adenomas correlated with the presence of CB1, being elevated in the tu moral samples positive for CB1 and lower in the samples in which no or low levels of CB1 were found. The results of this study point to a direct role of cannabinoids in the regulation of human pituitary hormone secretion.